Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Divergent Asymmetric Syntheses of Podophyllotoxin and Related Family Members via Stereoselective Reductive Ni-Catalysis Jian Xiao,† Xiao-Wei Cong,† Gui-Zhen Yang,† Ya-Wen Wang,†,‡ and Yu Peng*,†,‡ †
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, Gansu 730000, China School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China
‡
S Supporting Information *
ABSTRACT: A nickel-catalyzed reductive cascade approach to the efficient construction of diastereodivergent cores embedded in podophyllum lignans is developed for the first time. Their gram-scale access paved the way for unified syntheses of naturally occurring podophyllotoxin and other members.
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Scheme 1. Reductive Cyclization Logic to Podophyllotoxin
hile recent years have witnessed impressive developments in the area of nickel-catalyzed reductive coupling,1 this carbon−carbon formation method has not yet successfully been applied within the context of natural product synthesis. Moreover, the state-of-the art in this field has mainly concerned intermolecular couplings,2 while less attention was paid to fully intramolecular reactions3 and stereocontrolled tandem cyclizations, which our group focused on.4 Further demonstration of the total synthesis of bioactive natural products and pharmaceuticals still remains elusive and, thus, is in high demand.5 Podophyllotoxin [PT (1), Scheme 1], as a representative aryltetralin lignan6 of the podophyllum family, has received widespread attention from the research community. This molecule can be used for the treatment of angogenital warts, and its derivatives have also been used as chemotherapy drugs, such as etoposide and teniposide for leukemia, lung, and testicular cancer.7 Historically, PT molecules featuring strained trans-ring fusion, four contiguous chiral centers, and an axially locked C9-aryl substituent had been a challenging target. Some total syntheses of PT have been reported so far,8,9 continuously inspiring innovative tactics developments. Herein, we devised a new and concise route to 1. First, a Ni-catalyzed reductive cascade of dibromide 2 would lead to the generation of tetrahydronaphtho[2,3-c]furan (tetrahydronaphtho = THN) core 3 embedded in this kind of lignans. Formation of diastereodivergent products in such a single operation for the construction of two C−C bonds is a desired goal,10 therefore enabling access to any members of the podophyllum family in principle. Followed by the subsequent regioselective C−H bond oxidation, this class of tetralin lactone lignans, including 1 with four contiguous chiral centers, would be synthesized efficiently. © XXXX American Chemical Society
Our synthesis commenced with commercially available 6bromopiperonal (Scheme 2). The elongation of its carbon chain was carried out through Horner−Wadsworth−Emmons (HWE) olefination with triethyl phosphonoacetate, and the generated ester could be converted into the corresponding acyl chloride by saponification and the next reaction with pivaloyl chloride. The next stage was the introduction of a chiral auxiliary, which was completed by a condensation between the resulting acyl chloride and (S)-4-phenyl-2-oxazolidinone in 10 g scale and a good Received: February 4, 2018
A
DOI: 10.1021/acs.orglett.8b00408 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 2. Gram-Scale Syntheses of Stereodivergent Cores in Podophyllum Lignans
half-chair conformation (8b), as shown in Scheme 3. With gram amounts of diastereodivergent 9a and 9b in hand, eight natural products in the podophyllum family could be synthesized after a series of oxidation events (Scheme 4).
overall yield. The crucial asymmetric conjugate addition reaction11 was achieved by subjection of an arylcopper(I) reagent in situ generated from (3,4,5-trimethoxyphenyl)magnesium bromide to the above α,β-unsaturated acyl oxazolidinone 4, with excellent diastereocontrol (5, dr = 97:3) and 80% yield. This remote chirality-controlled transformation could be scaled up to 8 g without significant loss of the efficiency. More importantly, ent-5 could also be easily obtained, in principle, from similar reactions with (R)-4-phenyl-2-oxazolidinone, therefore demonstrating a potentially enantiodivergent feature of this approach for the construction of a diaryl methine center.12 The chiral auxiliary in 5 was then removed through reduction mediated by NaBH4, and the optical purity of the resulting alcohol S1 (Supporting Information) was determined as 93% ee. The subsequent oxidation and acetalization gave 6 in nearly quantitative yield. Upon exposure of this acetal to a mixture of TMSOTf and DIPEA,13 β-elimination occurred to provide the enol ether 7 as a Z/E mixture in 67% (85% brsm) yield. The site-selective bromination at the double bond proved quite challenging. The initial screening experiments with various bromonium reagents (NBS, Br2, et al.), including BDSB adapted by Snyder,14 always led to overbromination products, mainly due to reaction on the electron-rich benzene ring. After extensive optimization studies, we were pleased to find that upon treatment of enol ether 7 with 2,4,4,6-tetrabromo-2,5-cyclohexadienone (TBCD)15 in CH2Cl2 at 0 °C, the desired β-bromo acetals 8 were produced as an inseparable mixture in 76% isolated yield under 4 g scale. By slightly modifying the reaction conditions in our relevant studies,4h the expected tandem cyclization of 8 proceeded well to give cis-THN[2,3-c]furan 9a and trans-THN[2,3-c]furan 9b, which could be separated by flash column chromatography. Excellent stereoselectivities in this Nicatalyzed reductive cyclization4h could be attributed to the respective adoption of the pseudoboat conformation (8a) and
Scheme 3. Rationalization of Stereoselective Cyclization
The conversion of an acetal moiety in 9a or 9b to the corresponding lactone was done by initial hydrolysis and subsequent oxidation of the resulting lactol intermediate.16 (+)-Deoxypicropodophyllin (10) and (+)-isodeoxypodophyllotoxin (11) were thus obtained, respectively. Both their optical rotation and spectroscopic data (Tables S1 and S2) were consistent with previous reports.16,17 Epimerization at C9a in 10 under the enolization/quench conditions (LDA, THF, −78 °C then glacial acetic acid)18 led to cytotoxic (−)-deoxypodophyllotoxin (12), whose spectral data (Table S4) and optical rotation were in agreement with the literature as well.16,19 A single-crystal analysis of 12 further confirmed its structure (Figure 1, left; selected H atoms have been omitted for clarity). B
DOI: 10.1021/acs.orglett.8b00408 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 4. Divergent Syntheses of Natural Podophyllotoxin and Its Congeners
outcome was not clear at present. Eventually, this problem was solved by the ring opening of γ-lactone and the oxidation sequence (right side in Scheme 4). In this regard, treatment of all trans-THN[2,3-c]furanone 11 with H2SO4 (1 N) in reflux MeOH provided γ-hydroxyl ester 15 (not shown), which could be converted into silyl ether 16 by the protection of TBSCl in 93% overall yield. The ketone 17 was thus generated through a regioselective benzyl oxidation22 with a mixture of 3,5-dimethylpyrazole and CrO3.23 Since ketoester 17 was a known compound (Table S9) in the previous synthesis of (−)-picropodophyllin (18) and (−)-picropodophyllone (19) by Meyers,9a the demonstrated route here also constituted a formal synthesis for these two natural products. In summary, we have developed a nickel-catalyzed fully intramolecular reductive coupling method for the sequential construction of C−C bonds in stereodivergent THN[2,3-c]furan scaffolds of antineoplastic aryltetralin lactone lignans. In particular, this tandem cyclization led to expeditious syntheses of several closely related podophyllum members, including naturally occurring podophyllotoxin.
Figure 1. X-ray crystal structures of deoxypodophyllotoxin (left, 12) and podophyllotoxone (right, 14).
The next goal was an introduction of C4 hydroxyl, which was expected to be regio- and stereoselective. This formal benzyl C− H oxidation was accomplished in 81% overall yield through radical bromination20 under visible-light irradiation, followed by the hydrolysis of the resulting labile bromide during column chromatography on silica gel. As shown in Table S5, 1H NMR spectra of the synthetic (−)-epipodophyllotoxin (13) were in accord with data reported by Linker.21 The oxidation of 13 with PDC furnished the synthesis of (−)-podophyllotoxone (14),9g,h whose absolute stereochemistry was determined by the singlecrystal analysis (Figure 1, right; selected H atoms have been omitted for clarity). Upon subjection of 14 to L-selectride in THF at −78 °C, stereospecific reduction of the ketone carbonyl took place to give 87% of natural podophyllotoxin (1), and its 1H NMR data (Table S8) were consistent with previous reports.9e,g In order to access the corresponding natural products with a higher-oxidation level from 11, an attempted reaction by a similar operation like that of 12 to 13 was pursued, but surprisingly none of the desired products were observed. The exact reason for this
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b00408. Experimental procedures, characterization data (PDF) Copies of 1H/13C NMR (PDF) Accession Codes
CCDC 1811057−1811058 contain the supplementary crystallographic data for this paper. These data can be obtained free of C
DOI: 10.1021/acs.orglett.8b00408 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Yu Peng: 0000-0002-3862-632X Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by the NNSFC (Nos. 21472075 and 21772078). We thank Prof. Xuan Tian (Lanzhou University) for his generous donation of natural podophyllotoxin sample.
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REFERENCES
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DOI: 10.1021/acs.orglett.8b00408 Org. Lett. XXXX, XXX, XXX−XXX
